Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a process and intermediates useful in the preparation of certain pyrido-pyrimidine compounds, which act as mTOR kinase inhibitors, to salt forms thereof, and their formulation, particularly in tablet form, and use thereof.
• PBK phosphatidylinositol 3 -kinase
• AKT phosphatidylinositol 3 -kinase
• mTOR the mammalian target of rapamycin (alternatively referred to as FRAP (FKBP 12 and rapamycin associated protein), RAFTl (rapamycin and FKBP 12 target 1), RAPTl (rapamycin target 1) - all derived from the interaction with the FK-506-binding protein FKBP 12, and SEP (sirolimus effector protein)).
• FRAP FKBP 12 and rapamycin associated protein
• RAFTl rapamycin and FKBP 12 target 1
• RAPTl rapamycin target 1 - all derived from the interaction with the FK-506-binding protein FKBP 12, and SEP (sirolimus effector protein)
• mTOR is a mammalian serine/threonine kinase of approximately 289 kDa in size and a member of the evolutionary conserved eukaryotic TOR kinases (refs. 1-4).
• the mTOR protein is a member of the PB -kinase like kinase (PIKK) family of proteins due to its C-terminal homology (catalytic domain) with PB-kinase and the other family members, e.g. DNA- PKcs (DNA dependent protein kinase), ATM (Ataxia-telangiectasia mutated).
• mTOR In addition to a catalytic domain in the C-terminus, mTOR contains a FKBP12/rapamycin complex binding domain (FRB). At the N-terminus up to 20 HEAT (Huntingtin, EF3, alpha regulatory subunit of PP2A and TOR) motifs are found whilst more C-terminal is a FAT (FRAP-ATM-TRRAP) domain, and at the extreme C-terminus of the protein an additional FAT domain is found (FAT-C) (refs. 5,6).
• FAT FAT
• TOR has been identified as a central regulator of both cell growth (size) and proliferation, which is in part governed by translation initiation.
• S6K1 S6-kinase
• Cap-dependant translation is regulated by the phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1 (PHAS-I)). This modification prevents PHAS-I binding eIF4E, thereby permitting formation of an active eIF4F translation complex (reviewed in refs. 10,11,12).
• PBK/ AKT signalling cascade lies upstream of mTOR and this has been shown to be deregulated in certain cancers and results in growth factor independent activation in, for example, PTEN deficient cells.
• mTOR lies at the axis of control for this pathway and inhibitors of this kinase (e.g. sirolimus (rapamycin or Rapamune ) and everolimus (RADOOl or Certican )) are already approved for immunosuppression and drug eluting stents (reviewed in refs. 13, 14), and are now receiving particular interest as novel agents for cancer treatment.
• Tumour cell growth arises from the deregulation of normal growth control mechanisms such as the loss of tumour suppressor function(s).
• One such tumour suppressor is the phosphatase and tensin homologue deleted from chromosome ten (PTEN).
• PTEN phosphatase and tensin homologue deleted from chromosome ten
• MMAC multiple advanced cancers
• PI3K converts phosphatidylinositol 4,5, bisphosphate (PIP2) to phosphatidylinositol 3,4,5, triphosphate (PIP3) whilst PTEN is responsible for removing the 3' phosphate from PIP3 producing PIP2.
• PIP3-K and PTEN act to maintain an appropriate level of PIP3 which recruits and thus activates AKT (also known as PKB) and the downstream signalling cascade that is then initiated. In the absence of PTEN, there is inappropriate regulation of this cascade, AKT becomes effectively constitutively activated and cell growth is deregulated.
• mTOR rapamycin
• rapamycin potently inhibits proliferation or growth of cells derived from a range of tissue types such as smooth muscle, T-cells as well as cells derived from a diverse range of tumour types including rhabdomyosarcoma, neuroblastoma, glioblastoma and medulloblastoma, small cell lung cancer, osteosarcoma, pancreatic carcinoma and breast and prostate carcinoma (reviewed in ref. 20).
• Rapamycin has been approved and is in clinical use as an immunosuppressant, its prevention of organ rejection being successful and with fewer side effects than previous therapies (refs. 20, 21). Inhibition of mTOR by rapamycin and its analogues (RADOOl, CCI-779) is brought about by the prior interaction of the drug with the FK506 binding protein, FKBP 12. Subsequently, the complex of FKBPl 2/rapamycin then binds to the FRB domain of mTOR and inhibits the downstream signalling from mTOR.
• PBK potent but non-specific inhibitors of PBK, LY294002 and wortmannin
• wortmannin also have been shown to inhibit the kinase function of mTOR but act through targeting the catalytic domain of the protein (ref. 21). Further to the inhibition of mTOR function by small molecules targeted to the kinase domain, it has been demonstrated that kinase dead mTOR cannot transmit the upstream activating signals to the downstream effectors of mTOR, PHAS-I or p70S6 kinase (ref. 22). It is also shown that not all functions of mTOR are rapamycin sensitive and this may be related to the observation that rapamycin alters the substrate profile of mTOR rather than inhibiting its activity per se (ref. 23).
• a catalytic inhibitor of mTOR may be a more effective antagonist of cancer cell proliferation and survival and that rapamycin may be more useful in combination with agents that can compensate for its failure to completely disrupt pathway signalling (Choo and Blenis, Cancer Cell (2006) 9, 77-79; Hay, Cancer Cell (2005) 8, 179-183). Therefore, it is proposed that a kinase domain directed inhibitor of mTOR may be a more effective inhibitor of mTOR.
• rapamycin and its derivatives have been shown to potentiate the cytotoxicity of a number of chemotherapies including cisplatin, camptothecin and doxorubicin (reviewed in ref. 20). Potentiation of ionising radiation induced cell killing has also been observed following inhibition of mTOR (ref. 24).
• chemotherapies including cisplatin, camptothecin and doxorubicin
• pharmacological inhibitors of mTOR kinase should be of therapeutic value for treatment of the various forms of cancer comprising solid tumours such as carcinomas and sarcomas and the leukaemias and lymphoid malignancies.
• inhibitors of mTOR kinase should be of therapeutic value for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva,
• Renal cell carcinoma in particular has been identified as sensitive to the rapamycin derivative CCI-779, resulting from a loss of VHL expression (Thomas et al. Nature Medicine (2006) 12, 122-127).
• Tumours that have lost the promyelocytic leukaemia (PML) tumour suppressor have also been shown to be sensitive to inhibition of mTOR by rapamycin as a consequence of disruption of the regulation of the mTOR signalling pathway (Bernadi, Nature (2006) 442, 779-785) and the use of an mTOR kinase inhibitor in these diseases should be of therapeutic value.
• PML promyelocytic leukaemia
• Rapamycin has been demonstrated to be a potent immunosuppressant by inhibiting antigen-induced proliferation of T cells, B cells and antibody production (Sehgal, Transplantation
• mTOR kinase inhibitors may also be useful immunosuppressives. Inhibition of the kinase activity of mTOR may also be useful in the prevention of restenosis, that is the control of undesired proliferation of normal cells in the vasculature in response to the introduction of stents in the treatment of vasculature disease (Morice et al. New England Journal of Medicine (2002) 346. 1773-1780). Furthermore, the rapamycin analogue, everolimus, can reduce the severity and incidence of cardiac allograft vasculopathy (Eisen et al, New England Journal of Medicine (2003) 349, 847- 858).
• mTOR kinase inhibitors are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer.
• R 1 is hydrogen or OR 3 ;
• R 2 is CH 2 OR 4 , CN, CO 2 R 5 or CONR 6 R 7 ;
• R is Ci_4alkyl group;
• R 4 is a -COR 8 group wherein R 8 is a secondary C 3 _ 6 alkyl or tertiary C 4 _ 6 alkyl group;
• R 5 is a Ci_ 4 alkyl, a carbocyclyl, a carbocyclylCi_ 4 alkyl, a heterocyclyl or heterocyclylCi_ 4 alkyl group which is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci_6alkoxyCi_6alkyl, Ci_6alkoxyCi_ ⁇ alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino
• R 7 is Ci_ 4 alkyl group which is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci_6alkoxyCi_6alkyl, Ci_6alkoxyCi_ ⁇ alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (Ci_6alkyl)aminoCi_ 6 alkyl, bis(Ci_ 6 alkyl)aminoCi_ 6 alkyl, cyanoCi_ 6 alkyl, d_ 6 alkylsulfonyl, C 1- 6alkylsulfonylamino, Ci_6alkylsulfon
• R 1 is hydrogen or OR 3 ;
• R 2 is CH 2 OR 4 , CN, CO 2 R 5 or CONR 6 R 7 ;
• R is Ci_ 4 alkyl group
• R 4 is a -COR 8 group wherein R 8 is a secondary C 3 _ 6 alkyl or C 4 _ 6 tertiary alkyl group;
• R 5 is a Ci_ 4 alkyl, a carbocyclyl, a carbocyclylCi_ 4 alkyl, a heterocyclyl or heterocyclylCi_ 4 alkyl group which is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci_6alkoxyCi_6alkyl, Ci_6alkoxyCi_ ⁇ alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (C
• Ci_6alkylsulfonylamino Ci_6alkylsulfonyl(Ci_6alkyl)amino, sulfamoyl, Ci_6alkylsulfamoyl, bis(Ci_6alkyl)sulfamoyl, Ci_6alkanoylamino, Ci_6alkanoyl(Ci_6alkyl)amino, carbamoyl, Ci_ 6alkylcarbamoyl and bis(Ci_6alkyl)carbamoyl;
• R 6 is hydrogen or Ci_ 4 alkyl group which is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_ 6 alkyl, haloCi_ 6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci_ 6 alkoxyCi_ 6 alkyl, Ci_6alkoxyCi_6alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (C 1- 6 alkyl)aminoCi_ 6 alkyl, bis(Ci_ 6 alkyl)aminoCi_ 6 alkyl, cyanoCi_ 6 alkyl, Ci_ 6 alkylsulfonyl, C 1- 6 alkylsulfonylamino, Ci_6alkylsulfony
• R 7 is Ci_ 4 alkyl group which is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci_6alkoxyCi_6alkyl, Ci_6alkoxyCi_ ⁇ alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (Ci_6alkyl)aminoCi_ ⁇ alkyl, bis(Ci_ 6 alkyl)aminoCi_ 6 alkyl, cyanoCi_ 6 alkyl, Ci_ 6 alkylsulfonyl, C 1- 6 alkylsulfonylamino, Ci_6alkylsulfon
• L is a leaving group selected from NR a R b , OR C , SR d and halogen, and wherein R a , R b , R c and R d are each independently hydrogen or a group selected from Ci_ 6 alkyl, a carbocyclyl, a carbocyclylCi_ 6 alkyl, a heterocyclyl and heterocyclylCi_ 6 alkyl group which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_ 6 alkyl, haloCi_ 6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci_ 6 alkoxyCi_ 6 alkyl, Ci_6alkoxyCi_6alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, bis
• the 6-substituted uracil equivalent is a 6-aminouracil or 6- aminothiouracil or derivatives thereof.
• 6-aminouracil and derivatives thereof, include compounds of formula
• R N1 and R N2 each independently are hydrogen or a protecting group, for example a benzyl group.
• 6-aminothiouracil and derivatives thereof, include compounds of formula
• R N3 and R N4 each independently are hydrogen or a protecting group, for example a benzyl group.
• any protecting groups may be optionally removed in a further step to give a compound of formula 1.
• the 6-substituted uracil equivalent may result from the reaction of ammonia, and a 6-substituted uracil wherein the substituent is Ci_6alkyloxy, a carbocyclyloxy, a carbocyclylCi_ 6 alkyloxy, Ci_ 6 alkylthio, a carbocyclylthio, a carbocyclylCi_6alkylthio group.
• the process may be carried out in the presence of a solvent, for example water miscible polar solvents such as dimethylformamide, N-methylpyrollidone, dimethylsulphoxide or sulpholane.
• the process of the present invention may be carried out in the presence of an acid, for example an organic acid such as acetic acid.
• the compound of Formula 1 is isolated as the potassium salt by reaction with a potassium base, such as potassium carbonate or potassium hydroxide.
• the potassium salt is precipitated and collected, for example, by filtration. The compound of formula 1 can then be regenerated from the potassium salt by treatment with acid, for example citric acid.
• R 1 is hydrogen or OR 3 ;
• R 2 is CH 2 OR 4 , CN, CO 2 R 5 or CONR 6 R 7 ;
• R 3 is Ci_ 4 alkyl group
• R 4 is a -COR 8 group wherein R 8 is a secondary C 3 _ 6 alkyl or tertiary C 4 _ 6 alkyl group;
• R 5 is Ci_ 4 alkyl group
• R 6 is hydrogen or Ci_ 4 alkyl group
• R 7 is Ci_ 4 alkyl group; comprising reacting a compound of Formula 2a
• R 1 is hydrogen or OR 3 ;
• R 2 is CH 2 OR 4 , CO 2 R 5 or CONR 6 R 7 ;
• R is Ci_ 4 alkyl group
• R 4 is a -COR 8 group wherein R 8 is a secondary C 3 _ 6 alkyl or tertiary C 4 _ 6 alkyl group;
• R 5 is Ci_ 4 alkyl group
• R 6 is hydrogen or Ci_ 4 alkyl group
• R 7 is Ci_ 4 alkyl group; and R a , R b are each independently hydrogen or a group selected from Ci_ 6 alkyl, a carbocyclyl, a carbocyclylCi_ 6 alkyl, a heterocyclyl and heterocyclylCi_ 6 alkyl group which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci_6alkoxyCi_6alkyl, Ci_6alkoxyCi_6alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (Ci_6alkyl)aminoCi_6alkyl, bis(
• the compound of Formula 2 is added to a mixture of 6- aminouracil and an acid, for example an organic such as acetic acid.
• the compound of Formula 1 is isolated as the potassium salt by reaction with a potassium base, such as potassium carbonate or potassium hydroxide.
• a potassium base such as potassium carbonate or potassium hydroxide.
• the potassium salt is precipitated and collected, for example, by filtration.
• the compound of formula 1 can then be regenerated from the potassium salt by treatment with acid, for example citric acid.
• a compound of Formula 2 where L is a leaving group selected from NR a R b and OR C may be prepared by reacting a compound of Formula 3
• R 1 is hydrogen or OR 3 ;
• R 2 is CH 2 OR 4 , CN, CO 2 R 5 or CONR 6 R 7 ;
• R is Ci_4 alkyl group;
• R 4 is a -COR 8 group wherein R 8 is a secondary C 3 _ 6 alkyl or C 4 _ 6 tertiary alkyl group;
• R 5 is a Ci_ 4 alkyl, a carbocyclyl, a carbocyclylCi_ 4 alkyl, a heterocyclyl or heterocyclylCi_ 4 alkyl group which is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_ 6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci_ 6 alkoxyCi_ 6 alkyl, Ci_ 6 alkoxyCi_ ⁇ alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (Ci_6alkyl)aminoCi_ ⁇ alkyl, bis(Ci_ 6 alkyl)aminoCi_ 6 alkyl, cyanoCi
• R 6 is hydrogen or Ci_4 alkyl group which is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_ 6 alkyl, haloCi_ 6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci_ 6 alkoxyCi_ 6 alkyl, Ci_6alkoxyCi_6alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (C 1- 6 alkyl)aminoCi_ 6 alkyl, bis(Ci_ 6 alkyl)aminoCi_ 6 alkyl, cyanoCi_ 6 alkyl, Ci_ 6 alkylsulfonyl, Ci_ 6 alkylsulfonylamino, Ci_6alkylsulfony
• R 7 is Ci_4 alkyl group which is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_ 6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci_ 6 alkoxyCi_ 6 alkyl, Ci_ 6 alkoxyCi_ ⁇ alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (Ci_6alkyl)aminoCi_ ⁇ alkyl, bis(Ci_ 6 alkyl)aminoCi_ 6 alkyl, cyanoCi_ 6 alkyl, Ci_ 6 alkylsulfonyl, Ci_
• aminomethylene derivative is substituted alkoxy bis(amino)methane such as Bredereck's reagent (t-butoxy bis(dimethylamino)methane).
• the aminomethylene derivative is a substituted formamide acetal, for example a dimethyl formamide dialkyl acetal such as dimethyl formamide dimethyl acetal.
• the reaction of a compound of Formula 3 with an aminomethylene derivative may be carried out in the presence of solvent, for example a polar aprotic solvent such as N- methylpyrollidone or dimethyl formamide, or in mixtures of a polar aprotic solvent and non-polar solvents such as aromatic solvents such as toluene.
• solvent for example a polar aprotic solvent such as N- methylpyrollidone or dimethyl formamide, or in mixtures of a polar aprotic solvent and non-polar solvents such as aromatic solvents such as toluene.
• the orthoformate is trimethylorthoformate.
• a compound of Formula 2 where L is a leaving group selected from SR d and halogen may be prepared from the corresponding phenyl acetylenic ketone by for example hydrohalogenation, or by reaction withy thiols, (see Yakahiko Nishio et. al., J.C.S Perkin I, 1981, 934-938; Jose Juan Conde et. AL, Tetrahedron Letters 2000 (41) 4709-4711; or Shengming Ma et al., J.Org.Chem. 1992 (57) 709-713).
• R 1 is hydrogen or OR 3 ;
• R 2 is CH 2 OR 4 , CN, CO 2 R 5 or CONR 6 R 7 ;
• R 3 is Ci_4 alkyl group
• R 4 is a -COR 8 group wherein R 8 is a secondary C 3 _ 6 alkyl or C 4 _ 6 tertiary alkyl group;
• R 5 is a Ci_ 4 alkyl, a carbocyclyl, a carbocyclylCi_ 4 alkyl, a heterocyclyl or heterocyclylCi_ 4 alkyl group which is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci_6alkoxyCi_6alkyl, Ci_6alkoxyCi_ 6 alkoxy, amino, Ci_ 6 alkylamino, bis(Ci_ 6 alkyl)amino, aminoCi_ 6 alkyl, (Ci_ 6 alkyl)aminoCi_ ⁇ alkyl, bis(Ci_ 6 alkyl)aminoCi_ 6 alkyl, cyanoCi_
• R 6 is hydrogen or Ci_ 4 alkyl group which is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_ 6 alkyl, haloCi_ 6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci_ 6 alkoxyCi_ 6 alkyl, Ci_ 6 alkoxyCi_ 6 alkoxy, amino, Ci_ 6 alkylamino, bis(Ci_ 6 alkyl)amino, aminoCi_ 6 alkyl, (C 1- 6 alkyl)aminoCi_ 6 alkyl, bis(Ci_ 6 alkyl)aminoCi_ 6 alkyl, cyanoCi_ 6 alkyl, Ci_ 6 alkylsulfonyl, Ci_ 6 alkylsulfonylamino, Ci_6alkylsulfony
• R 1 is hydrogen or OR 3 ;
• R 2 is CH 2 OR 4 , CN, CO 2 R 5 or CONR 6 R 7 ;
• R 3 is Ci_ 4 alkyl group
• R 4 is a -COR 8 group wherein R 8 is a secondary C 3 _ 6 alkyl or C 4 _ 6 tertiary alkyl group;
• R 5 is a Ci_ 4 alkyl, a carbocyclyl, a carbocyclylCi_ 4 alkyl, a heterocyclyl or heterocyclylCi_ 4 alkyl group which is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_ 6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci_ 6 alkoxyCi_ 6 alkyl, d_ 6 alkoxyCi_ ⁇ alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (Ci_6alkyl)aminoCi_ ⁇ alkyl, bis(Ci_ 6 alkyl)aminoCi_ 6 alkyl, cyanoC
• R 6 is hydrogen or Ci_ 4 alkyl group which is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_ 6 alkyl, haloCi_ 6 alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci_ 6 alkoxyCi_ 6 alkyl, Ci_6alkoxyCi_6alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (C 1- 6 alkyl)aminoCi_ 6 alkyl, bis(Ci_ 6 alkyl)aminoCi_ 6 alkyl, cyanoCi_ 6 alkyl, Ci_ 6 alkylsulfonyl, Ci_ 6alkylsulfonylamino, Ci_6alkylsulfony
• L is a leaving group
• R 1 is hydrogen or OR 3 ;
• R z is CH 2 OR 4 , CN, CO 2 R or CONR 6 0 ⁇ R7';.
• R 3 is Ci_4 alkyl group
• R 4 is a -COR 8 group wherein R 8 is a secondary C 3 _ 6 alkyl or tertiary C 4 _ 6 alkyl group;
• R 5 is Ci_ 4 alkyl group
• R 6 is hydrogen or Ci_4 alkyl group
• R 7 is Ci_4 alkyl group with an amino methylene derivative to give a compound of Formula 2a
• R 1 is hydrogen or OR 3 ;
• R 2 is CH 2 OR 4 , CO 2 R 5 or CONR 6 R 7 ;
• R 3 is Ci_ 4 alkyl group
• R 4 is a -COR 8 group wherein R 8 is a secondary C 3 _ 6 alkyl or tertiary C 4 _ 6 alkyl group;
• R 5 is Ci_4 alkyl group
• R 6 is hydrogen or Ci_4 alkyl group
• R 7 is Ci_4 alkyl group
• R a , R b are each independently hydrogen or a group selected from d_ 6 alkyl, a carbocyclyl, a carbocyclylCi_ 6 alkyl, a heterocyclyl and heterocyclylCi_ 6 alkyl group which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci_ 6 alkoxyCi_ 6 alkyl, Ci_ 6 alkoxyCi_ 6 alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (Ci_6alkyl)aminoCi_6alkyl, bis(Ci_ 6 alkyl)amino
• R a and R b together with the nitrogen atom to which they are attached form a 4- to 10- membered heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci_6alkoxyCi_6alkyl, Ci_6alkoxyCi_ ⁇ alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (Ci_6alkyl)aminoCi_ 6 alkyl, bis(Ci_ 6 alkyl)aminoCi_ 6 alkyl,
• Z is halogen or OSO 2 R 9 , where R 9 is perfluoroCi_4alkyl, and A " is a counterion, such as PF 6 " .
• halogenating agents include phosphorusoxychloride.
• enolate trapping agents include trifluoromethanesulphonyl chloride.
• R 1 is hydrogen or OR 3 ;
• R 2 is CH 2 OR 4 , CO 2 R 5 or CONR 6 R 7 ;
• R is Ci_4 alkyl group
• R 4 is a -COR 8 group wherein R 8 is a secondary C 3 _ 6 alkyl or tertiary C 4 _ 6 alkyl group;
• R is Ci_ 4 alkyl group
• R 6 is hydrogen or Ci_4 alkyl group
• R 7 is Ci_ 4 alkyl group with an amino methylene derivative to give a compound of Formula 2a
• R 1 is hydrogen or OR 3 ;
• R 2 is CH 2 OR 4 , CN, CO 2 R 5 or CONR 6 R 7 ;
• R is Ci_ 4 alkyl group
• R 4 is a -COR 8 group wherein R 8 is a secondary C 3 _ 6 alkyl or tertiary C 4 _ 6 alkyl group; R 5 is Ci_ 4 alkyl group;
• R 6 is hydrogen or Ci_ 4 alkyl group
• R 7 is Ci_ 4 alkyl group
• R a , R b are each independently hydrogen or a group selected from d_ 6 alkyl, a carbocyclyl, a carbocyclylCi_ 6 alkyl, a heterocyclyl and heterocyclylCi_ 6 alkyl group which group is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_6alkyl, Ci_6alkoxy, haloCi_6alkyl, haloCi_6alkoxy, hydroxyCi_ 6 alkyl, hydroxyCi_ 6 alkoxy, Ci_ 6 alkoxyCi_ 6 alkyl, Ci_ 6 alkoxyCi_ 6 alkoxy, amino, Ci_ 6 alkylamino, bis(Ci_ 6 alkyl)amino, aminoCi_ 6 alkyl, (Ci_ 6 alkyl)aminoCi_ 6 alkyl, bis(Ci_ 6 alkyl)amino
• R a and R b together with the nitrogen atom to which they are attached form a 4- to 10- membered heterocyclic ring wherein 1 , 2 or 3 ring carbon atoms is optionally replaced with N, O or S and which ring is optionally substituted by one or more substituent groups selected from halo, cyano, nitro, hydroxy, oxo, Ci_ 6 alkyl, Ci_ 6 alkoxy, haloCi_ 6 alkyl, haloCi_6alkoxy, hydroxyCi_6alkyl, hydroxyCi_6alkoxy, Ci_6alkoxyCi_6alkyl, Ci_6alkoxyCi_ ⁇ alkoxy, amino, Ci_6alkylamino, bis(Ci_6alkyl)amino, aminoCi_6alkyl, (Ci_6alkyl)aminoCi_ ⁇ alkyl, bis(Ci_ 6 alkyl)aminoCi_ 6 alkyl,
• Z is halogen or OSO 2 R 9 , where R 9 is perfluoroCi_4alkyl, and A " is a counterion, such as PF 6 " and iii) reacting a compound of Formula 2b with 6-aminouracil to give a compound of Formula 1.
• Compounds of Formula 1 may find use in the preparation of mTOR kinase inhibitors, for example the mTOR kinase inhibitors described in WO2007/060404 and WO2008/023161 .
• aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group.
• an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions
• Lewis acid such as aluminium trichloride
• modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl; hydrolysis of an ester to give an alcohol or acid; reduction of an ester to give an alcohol by for example using metal hydrides such as lithium borohydride, lithium aluminium hydride or diisobutylaluminium hydride; and reduction of a nitrile to give an alcohol by for example first carrying out reduction of the nitrile to an imine using metal hydrides, such as diisobutylaluminium hydride, followed by hydrolysis of the imine to give an aldehyde and reduction of the aldehyde using metal hydrides, such as sodium borohydride.
• metal hydrides such as lithium borohydride, lithium aluminium hydride or diisobutylaluminium hydr
• a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or te/t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
• the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
• a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
• a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as pivaloyl.
• the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
• an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
• an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
• a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyi group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoro acetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
• a base such as sodium hydroxide
• a tert-butyi group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoro acetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
• the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
• the compound of Formula 5 may be isolated as a salt.
• Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compound of Formula 5 and their pharmaceutically acceptable salts.
• Pharmaceutically acceptable salts of the invention may, for example, include acid addition salts of compound of Formula 5, as herein defined, wherein the compound of Formula 5 is sufficiently basic to form such salts, and base salts of compound of Formula 5, as herein defined, wherein the compound of Formula 5 is sufficiently acidic to form such salts.
• the compound of Formula 5 is isolated as a phosphate, sulphate, hydrogensulphate, malate, citrate, tartrate or fumarate salt.
• the compound of Formula 5 is isolated as a di-phosphate, D- tartrate or fumarate salt.
• the compound of Formula 5 is isolated as a fumarate salt.
• C p _ q alkyl includes both straight-chain and branched-chain alkyl groups.
• references to individual alkyl groups such as “propyl” are specific for the straight chain version only (i.e. n-propyl and isopropyl) and references to individual branched-chain alkyl groups such as "te/t-butyl” are specific for the branched chain version only.
• secondary C p _ q alkyl indicates branched-chain alkyl groups, where the branching is at the alpha carbon atom, for example “secondary C 3 _ 4 alkyl” .
• Ci_4alkyl includes Cialkyl (methyl), C 2 alkyl (ethyl), C 3 alkyl (propyl as n-propyl and isopropyl) and C 4 alkyl (n-butyl, sec-butyl, isobutyl and tert-butyi).
• C p _ q alkoxy comprises -O-C p _ q alkyl groups.
• C p _ q alkanoyl comprises -C(O)alkyl groups.
• halo includes fluoro, chloro, bromo and iodo.
• Carbocyclyl includes "aryl”, “C p _ q cycloalkyl” and “C p _ q Cycloalkenyl”.
• aryl is an aromatic monocyclic, bicyclic or tricyclic carbcyclyl ring system.
• Heterocyclyl includes “heteroaryl", “cycloheteroalkyl” and “cycloheteroalkenyl”.
• Heteroaryl is an aromatic monocyclic, bicyclic or tricyclic heterocyclyl, particularly having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are chosen from nitrogen, sulfur or oxygen where a ring nitrogen or sulfur may be oxidised.
• This specification may make use of composite terms to describe groups comprising more than one functionality. Unless otherwise described herein, such terms are to be interpreted as is understood in the art.
• carbocyclylC p _ q alkyl comprises C p _ q alkyl substituted by carbocyclyl
• heterocyclylC p _ q alkyl comprises C p _ q alkyl substituted by heterocyclyl
• bis(C p _ q alkyl)amino comprises amino substituted by 2 C p _ q alkyl groups which may be the same or different.
• HaloC p _ q alkyl is a C p _ q alkyl group that is substituted by 1 or more halo substituents and particularly 1, 2 or 3 halo substituents.
• other generic terms containing halo such as haloC p _ q alkoxy may contain 1 or more halo substituents and particularly 1 , 2 or 3 halo substituents.
• HydroxyC p _ q alkyl is a C p _ q alkyl group that is substituted by 1 or more hydro xyl substituents and particularly by 1, 2 or 3 hydroxy substituents.
• other generic terms containing hydroxy such as hydroxyC p _ q alkoxy may contain 1 or more and particularly 1, 2 or 3 hydroxy substituents.
• Cp_ q alkoxyC p _ q alkyl is a C p _ q alkyl group that is substituted by 1 or more C p _ q alkoxy substituents and particularly 1, 2 or 3 C p _ q alkoxy substituents.
• C p _ q alkoxy such as C p _ q alkoxyC p _ q alkoxy may contain 1 or more C p _ q alkoxy substituents and particularly 1, 2 or 3 C p _ q alkoxy substituents.
• substituents are chosen from “1 or 2", from “1, 2, or 3” or from “1, 2, 3 or 4" groups or substituents it is to be understood that this definition includes all substituents being chosen from one of the specified groups i.e. all substituents being the same or the substituents being chosen from two or more of the specified groups i.e. the substituents not being the same.
• Suitable values for any R group or any part or substituent for such groups include: for Ci_4alkyl: methyl, ethyl, propyl, butyl, 2-methylpropyl and tert-butyl; for Ci_ 6 alkyl: Ci_ 4 alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and hexyl; for C 3 _ 6 cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; for C 3 _ 6 CycloalkylCi_ 4 alkyl: cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; for aryl: phenyl and naphthyl; for arylCi_ 4 alkyl: benzyl, phenethyl, naphthylmethyl and naphthyle
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , R c , R d , L and X are as follows. Such values may be used where appropriate, in connect with any aspect of the invention, or part thereof, and with any of the definitions, claims or embodiments defined herein.
• R 1 is hydrogen or methyl.
• R 2 is -CH 2 OCOC(CH 3 ) 3 , -CN, -CO 2 CH 3 or -CO2NHCH 3
• R is methyl
• R 4 is -COR 8 wherein R 8 is C 4 _ 6 tertiary alkyl. In one aspect of the invention R 4 is -COC(CH 3 ) 3 .
• R 5 is Ci_ 4 alkyl, phenyl or benzyl group. In one aspect of the invention R 5 is methyl.
• R 6 is hydrogen or C 1-4 alkyl. In one aspect of the invention R 6 is hydrogen or methyl.
• R 6 is hydrogen
• R 7 is Ci_ 4 alkyl. In one aspect of the invention R 7 is methyl.
• R 8 is C 4-6 tertiary alkyl. In one aspect of the invention R 8 is -C(CH 3 ) 3 .
• R 9 is -CF 3 .
• R a is hydrogen or Ci_ 4 alkyl. In another aspect of the invention R a is hydrogen or methyl. In another aspect of the invention R a is methyl.
• R b is hydrogen or C 1-4 alkyl.
• R b is hydrogen or methyl. In another aspect of the invention R b is methyl.
• R c is selected from
• R d is selected from R a and R b
• only one of R a and R b is hydrogen.
• R a is hydrogen and R b is Ci_ 4 alkyl.
• R a is hydrogen and R b is methyl.
• R a and R b is Ci_ 4 alkyl. In another aspect of the invention R a and R b is methyl.
• R a and R b together with the atoms to which they are attached form a ring.
• L is NR a R b . In one aspect of the invention L is NMe 2 .
• X is chlorine or bromine.
• X is chlorine
• Z is chlorine or -OSO 2 CF 3 .
• Z is chlorine
• Z is -OSO 2 CF 3 .
• R 1 is OCH 3 ;
• R 2 is CH 2 OCOC(CHS) 3 or CO 2 CH 3 ; by one or more of the processes described hereinbefore,
• the processes described herein may be used to prepare a fumarate salt of (5- ⁇ 2,4-bis[(35)-3-methylmorpholin-4-yl]pyrido[2,3-J]pyrimidin-7-yl ⁇ -2- methoxyphenyl)methanol.
• a particular compound of formula 5a is (5- ⁇ 2,4-bis[(3S)-3-methylmorpholin-4- yl]pyrido[2,3-(i]pyrimidin-7-yl ⁇ -2-methoxyphenyl)methanol.
• the active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g.
• vaginal parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot, for example, subcutaneously or intramuscularly.
• the active compound While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g., formulation) comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
• a pharmaceutical composition e.g., formulation
• pharmaceutically acceptable carriers e.g., adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
• Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
• the active ingredient may be administered in the form of a tablet.
• a tablet may be made by conventional means, e.g. compression or moulding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g.
• Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
• a pharmaceutical composition which comprises a fumarate salt of a compound of Formula 5a with mannitol.
• a pharmaceutical composition which comprises a fumarate salt of a compound of Formula 5a, mannitol and dicalcium phosphate.
• a pharmaceutical composition which comprises a fumarate salt of a compound of Formula 5a, mannitol and dicalcium phosphate, wherein the weight ratio of mannitol: dicalcium phosphate is from about 10:1 to about 1 :1.
• the weight ratio of mannitol to dicalcium phosphate is from about 7.5 : 1 to about 3:1.
• the weight ratio of mannitol to dicalcium phosphate is about 7.5:1 to about 5:1.
• the weight ratio of mannitol to dicalcium phosphate is from about 3 : 1 to about 1 :1.
• the weight ratio of mannitol to dicalcium phosphate is about 2.35:1.
• Mannitol refers to mannitol as described in the European Pharmacopoeia (PhEur).
• the composition according to the invention may use any mannitol suitable for use in pharmaceutical compositions such as tablets.
• the mannitol has average particle size in the range of from about 25 to about 180 ⁇ m, for example about 50 to about 170 ⁇ m, for tablets containing a fumarate salt of a compound of Formula 5a.
• the mannitol has an average particle size of about 160 ⁇ m.
• the bulk (poured) density of the mannitol (prior to incorporation into the composition) is about 0.6 to about 0.7 g/cm and the tapped density is about 0.8 to about 0.9 g/cm .
• the bulk (poured) density is about 0.66 g/cm and the tapped density is about 0.85 g/cm .
• the mannitol is substantially free from moisture prior to incorporation into the composition according to the invention (for example containing less than 5, 2 or 1% by weight water).
• the mannitol contains about 0.1 to 0.5% by weight of water prior to incorporation into the composition, for example about 0.2%.
• Mannitol as used herein may also refer to mannitol sold under the trade name Pearlitol ® (ex Roquette Freres S. A.).
• the mannitol is Pearlitol ® 160C.
• Dicalcium phosphate refers to calcium hydrogen phosphate, anhydrous as described in the European Pharmacopoeia (PhEur).
• the composition according to the invention may use any dicalcium phosphate suitable for use in pharmaceutical compositions such as tablets.
• the bulk (poured) density of the dicalcium phosphate (prior to incorporation into the composition) is about 0.6 g/cm 3 to about 1 g/cm 3 and the tapped density is about 1.25 g/cm 3 to about 1.35 g/cm 3 .
• the tapped density is about 1.28 g/cm .
• the dicalcium phosphate is substantially free from moisture prior to incorporation into the composition according to the invention (for example containing less than 10, 5 or 3% by weight water). In another embodiment the dicalcium phosphate contains about 0.3 to 2% by weight of water prior to incorporation into the composition, for example about 1%. Dicalcium phosphate as used herein may also refer to dicalcium phosphate sold under the trade name Calipharm (ex Innophos, Inc.). In one embodiment the dicalcium phosphate is Calipharm A ® .
• the pharmaceutical composition additionally contains one or more disintegrants. In another aspect, the pharmaceutical composition additionally contains one disintegrant. In another aspect, the pharmaceutical composition additionally contains low- substituted hydroxypropyl cellulose (L-HPC). Any grade of L-HPC suitable for pharmaceutical formulation may be used, for example LH-21 (Shin Etsu Chemical Co.). In one aspect the pharmaceutical composition additionally contains one or more binders.
• L-HPC low- substituted hydroxypropyl cellulose
• Suitable binders include, for example, lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatine, polyvinylpyrollidone (PVP or Povidone) and sodium alginate.
• lactose starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatine, polyvinylpyrollidone (PVP or Povidone) and sodium alginate.
• PVP polyvinylpyrollidone
• the pharmaceutical composition additionally contains one binder selected from lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatine, polyvinylpyrollidone (Povidone) and sodium alginate.
• the pharmaceutical composition additionally contains hydroxypropyl cellulose.
• microcrystalline cellulose could act as a binder and/or a disintegrant as well as a filler.
• the pharmaceutical composition additionally contains one or more lubricants.
• Suitable lubricants include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnuba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and sodium stearyl fumarate.
• the pharmaceutical composition additionally contains one lubricant selected from magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnuba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and sodium stearyl fumarate.
• the pharmaceutical composition additionally contains magnesium stearate.
• the pharmaceutical composition contains from 2 to 50 % by weight of a fumarate salt of a compound of Formula 5a. For example it contains from 15 to 35% by weight of a fumarate salt of a compound of Formula 5 a. In one embodiment the composition contains 20 to 30 % by weight of a fumarate salt of a compound of Formula 5 a. In particular it contains 23 to 27 % by weight of a fumarate salt of a compound of Formula 5 a.
• the composition according to the invention such as a capsule or tablet, contains 12.5 mg of a fumarate salt of a compound of Formula 5a. In another aspect the composition, such as a capsule or tablet, contains 25 mg of a fumarate salt of a compound of Formula 5a. In another aspect the composition, such as a capsule or tablet, contains 125 mg of a fumarate salt of a compound of Formula 5a.
• the pharmaceutical composition contains from 50 to 95 % by weight of filler. In another aspect the composition contains from 60 to 75% by weight of filler. In particular, it contains 65 to 69 % by weight of filler.
• the filler is mannitol. In another aspect, the filler is mannitol and dicalcium phosphate. In one embodiment the composition contains about 35 to 60 % by weight of mannitol, for example about 45 to 49 % by weight. In another embodiment the composition contains about 15 to 25 % by weight of dicalcium, phosphate, for example about 18 to 22 % by weight. In particular, the composition contains 19.0 to 21.0 % by weight of dicalcium phosphate. In another embodiment the composition contains from about 45 to 49 % by weight of mannitol and about 18 to 22 % by weight of dicalcium phosphate.
• the pharmaceutical composition contains from 1 to 10 % by weight of disintegrant. In particular, it contains 6.5 to 7.5 % by weight of disintegrant.
• the pharmaceutical composition contains from 0 to 5 % by weight of binder. In particular, it contains no binder. Typically one or more lubricants will be present in an amount from 0.5 to 2.5 % by weight, particularly 0.75 to 2 % by weight and especially 0.75 to 1.25 % by weight.
• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising:
• dicalcium phosphate in an amount of 18.0 to 22.0 % by weight.
• composition comprising:
• mannitol in an amount of 45 to 49 % by weight (for example 45.5 to 48.5 % by weight);
• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising:
• a fumarate salt of a compound of Formula 5a in an amount of 23.0 to 27.0 % by weight; • mannitol in an amount of 45 to 49 % by weight (for example 45.5 to 48.5 % by weight); • dicalcium phosphate in an amount of 18.0 to 22.0 % by weight;
• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising:
• mannitol in an amount of 45 to 49 % by weight (for example 45.5 to 48.5 % by weight); • dicalcium phosphate in an amount of 18.0 to 22.0 % by weight;
• the invention in another aspect relates to a pharmaceutical composition
• a pharmaceutical composition comprising: • a fumarate salt of a compound of Formula 5a in an amount of 23.0 to 27.0 % by weight;
• mannitol in an amount of 45 to 49 % by weight (for example 45.5 to 48.5 % by weight);
• magnesium stearate in an amount of 0.75 to 2.0 % by weight (for example 0.75 to 1.25% by weight).
• compositions are described in terms of % by weight of components of the composition, the sum of the % by weight of all of the components of the composition is 100%.
• the invention relates to a pharmaceutical composition, as described herein, prepared by wet granulation.
• the tablets described herein may be prepared by granulation, in particular wet granulation.
• the drug substance, a compressible filler and other ingredients, if required, are mixed to a homogeneous composition then compressed in a tablet press to produce tablets.
• All materials used in a direct compression process must be carefully selected with regard to particle size distribution, density, physical form in order to avoid segregation during mixing and to ensure suitable flow and compression properties.
• Such properties may also be conferred by granulation, which is a process by which primary particles (powders) are made to adhere to form larger, multiparticulate entities called granules.
• Granulation normally commences after initial dry mixing of the powdered ingredients so that a fairly uniform distribution of ingredients through the mix is achieved.
• Granulation methods can be divided into two types, wet granulation methods that utilize a liquid to form the granules and dry methods that do not.
• Wet granulation involves mixing the components to be granulated as a dry mix (for example a fumarate salt of a compound of Formula 5a, diluent(s), disintegrant(s) and optionally a binder).
• a dry mix for example a fumarate salt of a compound of Formula 5a, diluent(s), disintegrant(s) and optionally a binder.
• the dry mix is then massed using a granulating fluid to form granules.
• Sufficient granulating fluid is added to the dry mix to form granules during the granulation process, for example 10 to 50% by weight, suitably 15 to 25% by weight, of granulating fluid is added to the dry mix during the granulation.
• the granulating fluid may contain a solvent, which can be removed by drying, and is non-toxic.
• the granulating fluid is water.
• the granulating fluid can be used alone or with a binding agent (binder) to ensure particle adhesion in the dry state.
• Binding agents can be added to the system as a binder solution (as part of the granulating fluid) or as dry material mixed with the primary powder particles (as part of the dry mix).
• the granulating liquid is added to the dry powder mix in a manner to provide a substantially uniform liquid content in the mixture, for example by spraying the liquid onto the powder during the granulation.
• Wet granulators are well known and any suitable granulator may be used to form the wet granules.
• wet granulator such as planetary mixers
• shear granulators such as planetary mixers
• high shear mixer granulators such as Vector, Fielder, Collette Gral or Diosna
• fluid bed granualtors such as Aeromatic or Glatt
• the resulting wet mass may be passed through a coarse mesh (for example a 9mm mesh) to remove any large lumps that may have formed during the granulation.
• the granules are dried to a suitable moisture content, typically less that 2% by weight water, using a suitable drying method such as fluid bed drying.
• the resulting granules are then optionally milled to give a more homogenous particle size distribution.
• dry granulation methods primary powder particles are aggregated under pressure (or compaction).
• a large tablet also known as a slug
• roller compaction the powder particles are compressed between two rollers to produce a sheet or 'ribbon' of material
• the compacted material is milled using a suitable milling technique to produce granular material.
• the granules can then be compressed in a standard tablet press to produce tablets.
• the granules might be used in a capsule composition or compressed to form a tablet.
• the granules may be blended with a lubricant and then compressed into tablets. A suitable coating may then be applied to the tablets as described herein.
• compositions prepared by a wet granulation process that is suitable for oral administration.
• the invention in another aspect relates to a pharmaceutical composition obtainable by a wet granulation process comprising a fumarate salt of a compound of Formula 5 a with mannitol and dicalcium phosphate.
• the present inventors have found that they are able to manufacture satisfactory batches of the preferred composition, using either a direct compression grade or a wet granulation grade of mannitol, by a wet granulation process.
• Direct compression grade mannitol for example Parteck M grades of mannitol supplied by Merck Chemicals Ltd.
• the average particle size of the direct compression grade mannitol is about 150 to 350 ⁇ m, for example 200 to 300 ⁇ m.
• the direct compression grade mannitol has a bulk (poured) density (prior to incorporation into the composition) of about 0.4 to 0.5 g/cm 3 l and the tapped density is about 0.55 g/cm 3 to about 0.65 g/cm 3 .
• TM TM TM include Parteck M200, Parteck M300, Pearlitol SD200 or Mannogem EZ. In one
• the mannitol is Parteck M200.
• "Wet granulation grade mannitol” generally has a more granular particle shape than direct compression grade mannitol.
• the wet granulation grade mannitol has
• TM an average particle size in the range of about 100 to 300 ⁇ m.
• Pearlitol 160 an average particle size in the range of about 100 to 300 ⁇ m.
• C supplied by Roquette Freres S.A. comprises cubic crystals having a mean diameter of 160 microns.
• the invention relates to a pharmaceutical composition obtainable by a wet granulation process comprising wet granulation of a fumarate salt of a compound of Formula 5 a with mannitol and dicalcium phopshate wherein direct compression grade mannitol is used in the wet granulation process.
• a pharmaceutical composition obtainable by a wet granulation process comprising wet granulation of a fumarate salt of a compound of Formula 5 a with mannitol and dicalcium phosphate wherein wet granulation grade mannitol is used in the wet granulation process.
• composition comprising a fumarate salt of a compound of Formula 5 a with mannitol and dicalcium phosphate is prepared by wet granulation, particularly wet granulation grade mannitol is used.
• the invention in another aspect relates to a pharmaceutical composition obtainable by a wet granulation process comprising wet granulation of a fumarate salt of a compound of Formula 5a, mannitol, dicalcium phosphate, L-Hydroxypropyl cellulose, optionally a binder and a lubricant.
• the invention relates to a pharmaceutical composition obtainable by a wet granulation process comprising wet granulation of a fumarate salt of a compound of Formula 5a, mannitol, dicalcium phosphate, L-hydroxypropyl cellulose, optionally a binder and magnesium stearate.
• a pharmaceutical composition obtainable by a wet granulation process comprising wet granulation of a fumarate salt of a compound of Formula 5a, mannitol, dicalcium phosphate, L-hydroxypropyl cellulose, optionally hydroxypropyl cellulose and a lubricant.
• the invention in another aspect relates to a pharmaceutical composition obtainable by a wet granulation process comprising wet granulation of a fumarate salt of a compound of Formula 5a, mannitol, dicalcium phosphate, L-hydroxypropyl cellulose, optionally hydroxypropyl cellulose and magnesium stearate.
• the invention in another aspect relates to a pharmaceutical composition obtainable by a wet granulation process comprising wet granulation of a fumarate salt of a compound of Formula 5 a, mannitol, dicalcium phosphate, L-hydroxypropyl cellulose and magnesium stearate.
• the invention relates to a pharmaceutical composition obtainable by a wet granulation process comprising wet granulation of a fumarate salt of a compound of Formula 5 a, mannitol, dicalcium phosphate, L-hydroxypropyl cellulose and optionally a binder.
• the invention relates to a pharmaceutical tablet composition obtainable by a wet granulation process comprising:
• step (iii) compressing the mixture from step (iii) into tablets.
• any of the mannitol, dicalcium phosphate, L-hydroxypropyl cellulose, binder and lubricants described herein may be used.
• any of the mannitol, dicalcium phosphate, L-hydroxypropyl cellulose, binder and lubricants described herein may be used.
• the mannitol is a wet granulation grade mannitol such as Pearlitol 160 C.
• the pharmaceutical composition is in a solid dosage form, such as a tablet or capsule.
• the pharmaceutical composition is in the form of a tablet.
• the composition is in the form of a tablet designed for immediate release.
• the immediate release tablet will disintegrate quickly following administration as hereinbefore described. For example, typically represented by in- vitro dissolution times of about 2 to 20 minutes and typically 10 to 15 minutes.
• a process for the preparation of a pharmaceutical composition according to the invention comprising mixing a fumarate salt of a compound of Formula 5 a and the mannitol and dicalcium phosphate and forming the mixture into a unit dosage form such as a tablet or capsule.
• a fumarate salt of a compound of Formula 5 a and the mannitol and dicalcium phosphate and other optional ingredients as required such as a binder and disintegrant as hereinbefore described
• the mixture is granulated and formed into a suitable unit dosage form. Suitable granulation methods are as hereinbefore described.
• the mixture may be wet granulated as described herein.
• the binder such as hydroxypropyl cellulose may be incorporated into the mixture prior to granulation as a dry powder. Following granulation the granules may be dried and milled and, for example, compressed into a tablet as described hereinbefore.
• the composition is provided with a means for protecting a fumarate salt of a compound of Formula 5 a from light degradation as described hereinafter.
• the tablet is provided with a light protective coating as described hereinafter.
• step (ii) granulating the mixture formed in step (i) to form granules
• Additional excipients such as a disintegrant and binder may be included in the mixture in step (i) of the process as described hereinbefore and illustrated in the examples.
• the granulation step (ii) is a wet granulation as described hereinbefore.
• the granules are suitably dried prior to milling (if carried out) and subsequent compression into tablets.
• the process further comprises coating the tablets from step (v) with a film coating.
• the fumarate salt of a compound of Formula 5a exists in certain crystalline forms.
• a fumarate salt of a compound of Formula 5 a is in crystalline Form A.
• the invention relates to a pharmaceutical composition as hereinabove defined in which a fumarate salt of a compound of Formula 5 a is in a crystalline form.
• the invention in another aspect relates to a pharmaceutical composition as hereinabove defined comprising a fumarate salt of a compound of Formula 5 a wherein the salt is present in one or more crystalline forms.
• the invention relates to a pharmaceutical composition as hereinabove defined comprising a fumarate salt of a compound of Formula 5 a wherein the salt is present in one or more crystalline forms selected from Form A, Form B and Form C.
• the invention relates to a pharmaceutical composition as hereinbefore defined comprising a fumarate salt of a compound of Formula 5a substantially as crystalline Form A.
• the invention in another aspect relates to a pharmaceutical composition as hereinabove defined comprising a fumarate salt of (5- ⁇ 2,4-bis[(35)-3-methylmorpholin-4- yl]pyrido[2,3- ⁇ i]pyrimidin-7-yl ⁇ -2-methoxyphenyl)methanol wherein the salt is present in one or more crystalline forms selected from Form A, Form B and Form C.
• the invention relates to a pharmaceutical composition as hereinbefore defined comprising a fumarate salt of (5- ⁇ 2,4-bis[(3S)-3-methylmorpholin-4- yl]pyrido[2,3- ⁇ i]pyrimidin-7-yl ⁇ -2-methoxyphenyl)methanol substantially as crystalline Form A.
• Substantially as Form A means that there is greater than 95 % of Form A present. In particular there is greater than 96 % Form A. Particularly there is greater than 97 % Form A. In particular there is greater than 98 % Form A. Particularly there is greater than 99 % Form A. In particular there is greater than 99.5 % Form A. Particularly there is greater than 99.8 % Form A.
• a crystalline form of a fumarate salt of (5- ⁇ 2,4-bis[(35)-3-methylmorpholin-4-yl]pyrido[2,3-J]pyrimidin-7-yl ⁇ -2- methoxyphenyl)methanol having an XRD pattern comprising peaks at 2-theta ( ⁇ 1.5418 A) 6.0, 9.6, 12.2, 13.0 and 17.9.
• a crystalline form of a fumarate salt of (5- ⁇ 2,4-bis[(35)-3-methylmorpholin-4-yl]pyrido[2,3-(i]pyrimidin-7-yl ⁇ -2- methoxyphenyl)methanol having an XRD pattern comprising peaks at 2-theta ( ⁇ 1.5418 A) 6.0, 8.5, 9.6, 12.2, 13.0, 17.1, 17.7, 17.9, 18.3 and 19.3.
• a crystalline form of a fumarate salt of (5- ⁇ 2,4-bis[(35)-3-methylmorpholin-4-yl]pyrido[2,3-J]pyrimidin-7-yl ⁇ -2- methoxyphenyl)methanol having an XRD pattern comprising peaks at 2-theta ( ⁇ 1.5418 A) 6.3, 9.2, 10.1, 14.4 and 18.9.
• the crystalline form is not intended to be limited to the crystals that provide X-ray powder diffraction patterns identical to the X-ray powder diffraction patterns described herein.
• the present invention also includes any crystals providing X-ray powder diffraction patterns substantially the same as those described herein.
• a person skilled in the art of X-ray powder diffraction is able to judge the substantial similarity of X-ray powder diffraction patterns and will understand that differences may be the result of various factors for example measurement errors resulting from measurement conditions (such as equipment, sample preparation or the machine used); intensity variations resulting from measurement conditions and sample preparation; relative intensity variations of peaks resulting from variations in size or non-unitary aspect ratios of cyrstals; and the position of reflections which can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer, and surface planarity of the sample.
• measurement errors resulting from measurement conditions such as equipment, sample preparation or the machine used
• intensity variations resulting from measurement conditions and sample preparation relative intensity variations of peaks resulting from variations in size or non-unitary aspect ratios of cyrstals
• the position of reflections which can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer, and surface planar
• the tablet is suitably coated with a film.
• the composition is in the form of a tablet coated with a coating, suitably a film coating, comprising an iron oxide pigment.
• the iron oxide pigment is suitably present at about 0.025 to 1% by weight of the tablet.
• the iron oxide pigment is present at about 0.06% by weight of the tablet.
• the iron oxide pigment is present at about 0.6% by weight of the tablet.
• the tablet coating may
• TM be applied using for example a commercially available coating such as the Opadry films supplied by Colorcon Inc.
• the pharmaceutical composition is a tablet with a coating comprising one or more colouring agents.
• the pharmaceutical composition is a tablet with a coating comprising one colouring agent.
• the pharmaceutical composition is a tablet with a coating comprising an iron oxide pigment.
• the pharmaceutical composition is a tablet with a coating comprising iron oxide yellow.
• Coatings containing iron oxide pigments are commercially available, for example Opadry II Yellow (Colorcon85F38196 or Colorcon 85F32410), which may be applied to the tablet as an aqueous solution or suspension.
• the pharmaceutical composition is a tablet with a weight of coating between, for example 1 to 10%, such as 2 and 10% by weight of the tablet core weight, for example 3 to 6% by weight of the tablet core weight.
• the weight of coating is 3 to 4 % by weight of the tablet core weight.
• the weight of the coating is from about 1 to about 2% by weight of the tablet core weight.
• the pharmaceutical composition is a tablet with a coating comprising one or more film formers.
• the pharmaceutical composition is a tablet with a coating comprising one film former.
• the pharmaceutical composition is a tablet with a coating comprising a water-soluble film-former such as a polyvinyl alcohol (defined in the PhEur).
• the pharmaceutical composition is a tablet with a coating comprising one or more opacifiers. In another aspect, the pharmaceutical composition is a tablet with a coating comprising one opacif ⁇ er. In another aspect, the pharmaceutical composition is a tablet with a coating comprising titanium dioxide.
• the pharmaceutical composition is a tablet with a coating comprising one or more anti-tack agents. In another aspect, the pharmaceutical composition is a tablet with a coating comprising one anti-tack agent. In another aspect, the pharmaceutical composition is a tablet with a coating comprising talc.
• the pharmaceutical composition is a tablet with a coating comprising one or more plasticisers.
• the pharmaceutical composition is a tablet with a coating comprising one plasticiser.
• the pharmaceutical composition is a tablet with a coating comprising a polyethylene glycol plasticiser, for example Macrogol 3350 (defined in the PhEur).
• Tablet coating may be carried out using conventional methods well known in the art, for example coating in a pan coater.
• the film coat may be applied by spraying an aqueous suspension of the film former, opacifier, plasticiser and colouring agents onto the tablet cores.
• the invention in another aspect relates to a pharmaceutical composition
• a pharmaceutical composition comprising a fumarate salt of a compound of Formula 5 a which is a tablet with a coating comprising iron oxide yellow.
• the invention in another aspect relates to a pharmaceutical composition
• a pharmaceutical composition comprising a fumarate salt of a compound of Formula 5 a which is a tablet with a coating comprising polyvinyl alcohol, titanium dioxide, Macrogol 3350, iron oxide yellow and talc.
• the invention in another aspect relates to a tablet comprising a core comprising a a fumarate salt of a compound of Formula 5 a with mannitol and dicalcium phosphate and a coating comprising iron oxide yellow and talc.
• a tablet comprising a core comprising a fumarate salt of a compound of Formula 5 a with mannitol and dicalcium phosphate and a coating comprising polyvinyl alcohol, titanium dioxide, Macrogol 3350, iron oxide yellow and talc.
• the coating contains from 30 to 50 % by weight of film former. In particular, it contains 38.0 to 42.0 % by weight of film formers. In another aspect, the coating contains from 5 to 25 % by weight of opacifier. In one embodiment, it contains 8.0 to 12.0 % by weight of opacifier. In a further embodiment, it contains between 21.5 and 25.5 % by weight of opacifier.
• the coating contains from 10 to 30 % by weight of plasticiser. In particular, it contains 18.2 to 22.2 % by weight of plasticiser.
• the coating contains from 1 to 20 % by weight of iron oxide pigments. In one embodiment, it contains 13.0 - 17.0 % by weight of iron oxide pigments. In a further embodiment it contains 1.0 - 2.0 % by weight of iron oxide pigments.
• the coating contains from 14.5 to 15.1 % by weight of talc. In another aspect, the coating contains from 0.05 to 1.0% by weight of iron oxide pigment(s) and from 0.25 to 1.5 % by weight of titanium dioxide. For example in one embodiment a coating containing about 0.6% by weight of iron oxide and about 0.4% by weight of titanium dioxide, or in a further embodiment a coating containing about 0.06% by weight of iron oxide and about 0.94% by weight of titanium dioxide, wherein the weights are % weight relative to the weight of the tablet core to which the coating is applied.
• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a tablet core and a coating wherein the tablet core comprises:
• the coating on the tablet core comprises:
• the coating on the tablet core comprises:
• titanium dioxide in an amount of 22.0 to 25.0 % by weight of the coating.
• the invention in another aspect relates to a pharmaceutical composition
• a pharmaceutical composition comprising a core comprising a fumarate salt of a compound of Formula 5 a and, in one embodiment, a coating comprising: • a water-soluble film-former such as polyvinyl alcohol in an amount of 38.0 to 42.0 % by weight;
• a polyethylene glycol plasticiser such as Macrogol 3350 in an amount of 18.2 to 22.2 % by weight; • talc in an amount of 14.5 to 15.1 % by weight
• the coating comprises:
• a water-soluble film-former such as polyvinyl alcohol in an amount of 38.0 to 42.0 % by weight
• a polyethylene glycol plasticiser such as Macrogol 3350 in an amount of 18.2 to 22.2 % by weight
• the invention in another aspect relates to a pharmaceutical composition
• a pharmaceutical composition comprising a core comprising a fumarate salt of a compound of Formula 5 a and mannitol with optional dicalcium phosphate and, in one embodiment, a coating comprising: • a water-soluble film-former such as polyvinyl alcohol in an amount of 38.0 to 42.0
• a polyethylene glycol plasticiser such as Macrogol 3350 in an amount of 18.2 to 22.2 % by weight
• the coating comprises:
• a water-soluble film-former such as polyvinyl alcohol in an amount of 38.0 to 42.0 % by weight
• a polyethylene glycol plasticiser such as Macrogol 3350 in an amount of 18.2 to
• the invention relates to a pharmaceutical immediate release tablet composition
• a pharmaceutical immediate release tablet composition comprising a tablet core and a coating, wherein the tablet core comprises:
• a lubricant for example magnesium stearate
• the coating on the tablet core comprises an iron oxide pigment and wherein the coating is present in an amount of 3 to 6% by weight of the tablet core.
• the invention in another aspect relates to a pharmaceutical immediate release tablet composition
• a pharmaceutical immediate release tablet composition comprising a tablet core and a coating, wherein the tablet core comprises:
• dicalcium phosphate in an amount of 18.0 to 22.0 % by weight of the tablet core
• a coating on the tablet core comprising:
• a water-soluble film-former such as polyvinyl alcohol in an amount of 38.0 to 42.0 % by weight
• a polyethylene glycol plasticiser such as Macrogol 3350 in an amount of 18.2 to
• the coating comprises: • a water-soluble film-former such as polyvinyl alcohol in an amount of 38.0 to 42.0
• a polyethylene glycol plasticiser such as Macrogol 3350 in an amount of 18.2 to 22.2 % by weight
• titanium dioxide in an amount of 22.0 to 25.0 % by weight of the coating; wherein the weights are % by weight of the coating.
• the coating is present in an amount of 2.5 to 5% by weight of the tablet core, for example about 4.0% by weight of the tablet core. It is known that mTOR kinase and the PI3K enzymes have roles in tumourigenesis as well as numerous other diseases.
• Pharmaceutical composition comprising a fumarate salt of a compound of Formula 5 a may possess potent anti-tumour activity by way of inhibition of mTOR kinase.
• the compounds of the present invention are of value as anti-tumour agents.
• the compounds of the present invention are of value as antiproliferative, apoptotic and/or anti-invasive agents in the containment and/or treatment of solid and/or liquid tumour disease.
• the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR.
• the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours which are mediated alone or in part by mTOR.
• the compounds may thus be used to produce an mTOR enzyme inhibitory effect in a warm-blooded animal in need of such treatment.
• Inhibitors of mTOR kinase should be of therapeutic value for the treatment of proliferative disease such as cancer and in particular solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies and in particular for treatment of, for example, cancer of the breast, colorectum, lung (including small cell lung cancer, non- small cell lung cancer and bronchioalveolar cancer) and prostate, and of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias [including acute lymphoctic leukaemia (ALL) and chronic myelogenous leukaemia (CML)], multiple myeloma and lymphomas.
• proliferative disease such as cancer and in particular solid tumours such as carcinoma and sarcomas and the leukaemias
• Anti-cancer effects which are accordingly useful in the treatment of cancer in a patient include, but are not limited to, anti-tumour effects, the response rate, the time to disease progression and the survival rate.
• Anti-tumour effects of a method of treatment of the present invention include but are not limited to, inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to regrowth of tumour on cessation of treatment, slowing of disease progression.
• Anti-cancer effects include prophylactic treatment as well as treatment of existing disease.
• a mTOR kinase inhibitor, or a pharmaceutically acceptable salt thereof may also be useful for the treatment patients with cancers, including, but not limited to, haemato logic malignancies such as leukaemia, multiple myeloma, lymphomas such as Hodgkin's disease, non-Hodgkin's lymphomas (including mantle cell lymphoma), and myelodysplastic syndromes, and also solid tumours and their metastases such as breast cancer, lung cancer (non-small cell lung cancer (NSCL), small cell lung cancer (SCLC), squamous cell carcinoma), endometrial cancer, tumours of the central nervous system such as gliomas, dysembryoplastic neuroepithelial tumour, glioblastoma multiforme, mixed gliomas, medulloblastoma, retinoblastoma, neuroblastoma, germinoma and teratoma, cancers of the gastrointestinal tract such as gastric cancer, oesophag
• the compounds of the present invention and the methods of treatment comprising the administering or use of a mTOR kinase inhibitor, or a pharmaceutically acceptable salt thereof are expected to be particularly useful for the treatment of patients with lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and also for the treatment of patients with acute myeloid leukaemia.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for use as a medicament in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for use as a medicament in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use as a medicament in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for use in the production of an anti-pro liferative effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for use in the production of an anti-pro liferative effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use in the production of an anti-pro liferative effect in a warm- blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for use in the production of an apoptotic effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for use in the production of an apoptotic effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use in the production of an apoptotic effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of proliferative disease such as cancer.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of proliferative disease such as cancer.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of proliferative disease such as cancer.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for the production of an anti-pro liferative effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for the production of an anti-pro liferative effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for the production of an anti-pro liferative effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) in the manufacture of a medicament for use in the production of an antiproliferative effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol in the manufacture of a medicament for use in the production of an anti-pro liferative effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate in the manufacture of a medicament for use in the production of an anti-pro liferative effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for the production of an apoptotic effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for the production of an apoptotic effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for the production of an apoptotic effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) in the manufacture of a medicament for use in the production of an apoptotic effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol in the manufacture of a medicament for use in the production of an apoptotic effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate in the manufacture of a medicament for use in the production of an apoptotic effect in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with in the manufacture of a medicament for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of proliferative disease such as cancer.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol in the manufacture of a medicament for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of proliferative disease such as cancer.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate in the manufacture of a medicament for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of proliferative disease such as cancer.
• a method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a).
• a method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol.
• a method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol and dicalcium phosphate.
• a method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a).
• a method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol.
• a method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) in the manufacture of a medicament for use in the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol in the manufacture of a medicament for use in the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal such as man.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol and dicalcium phosphate in the manufacture of a medicament for use in the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal such as man.
• a method for the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a).
• a method for the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol.
• a method for the prevention or treatment of proliferative disease such as cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for use in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for use in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
• tumours which are sensitive to inhibition of mTOR kinase that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a).
• a method for the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells which comprises administering to said animal an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol.
• a method for the prevention or treatment of those tumours which are sensitive to inhibition of mTOR kinase that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells which comprises administering to said animal an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for use in providing a mTOR kinase inhibitory effect.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for use in providing a mTOR kinase inhibitory effect.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use in providing a mTOR kinase inhibitory effect.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) in the manufacture of a medicament for use in providing a mTOR kinase inhibitory effect.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol in the manufacture of a medicament for use in providing a mTOR kinase inhibitory effect.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate in the manufacture of a medicament for use in providing a mTOR kinase inhibitory effect.
• a method for providing a mTOR kinase inhibitory effect which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) .
• a method for providing a mTOR kinase inhibitory effect which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol.
• a method for providing a mTOR kinase inhibitory effect which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol and dicalcium phosphate.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for use in the treatment of solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for use in the treatment of solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use in the treatment of solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non- small cell lung cancer and bronchioalveolar cancer) and prostate.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• a fumarate salt of a compound of formula (5 a) for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• mannitol for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lympho
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, endometrium, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• a fumarate salt of a compound of formula (5 a) for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, endometrium, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, endometrium, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• mannitol for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, endometrium, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, endometrium, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• leukaemias including ALL and CML
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and also for the treatment acute myeloid leukaemia.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and also for the treatment acute myeloid leukaemia.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and also for the treatment acute myeloid leukaemia.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) in the manufacture of a medicament for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol in the manufacture of a medicament for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate in the manufacture of a medicament for use in the treatment of cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) in the manufacture of a medicament for use in the treatment of solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol in the manufacture of a medicament for use in the treatment of solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate in the manufacture of a medicament for use in the treatment of solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) in the manufacture of a medicament for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol in the manufacture of a medicament for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate in the manufacture of a medicament for use in the treatment of cancer of the breast, colorectum, lung (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar cancer) and prostate.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) in the manufacture of a medicament for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• leukaemias including ALL and CML
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol in the manufacture of a medicament for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• leukaemias including ALL and CML
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate in the manufacture of a medicament for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas.
• leukaemias including ALL and CML
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) in the manufacture of a medicament for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and also for the treatment acute myeloid leukaemia.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol in the manufacture of a medicament for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and also for the treatment acute myeloid leukaemia.
• a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate in the manufacture of a medicament for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and also for the treatment acute myeloid leukaemia.
• a method for treating cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a).
• a method for treating cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol.
• a method for treating cancer, inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate.
• a method for treating solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a).
• a method for treating solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol.
• a method for treating solid tumours such as carcinoma and sarcomas and the leukaemias and lymphoid malignancies in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate.
• a method for treating cancer of the breast, colorectum, lung (including small cell lung cancer, non- small cell lung cancer and bronchioalveolar cancer) and prostate in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a).
• a method for treating cancer of the breast, colorectum, lung (including small cell lung cancer, non- small cell lung cancer and bronchioalveolar cancer) and prostate in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol.
• a method for treating cancer of the breast, colorectum, lung (including small cell lung cancer, non- small cell lung cancer and bronchioalveolar cancer) and prostate in a warm blooded animal such as man that is in need of such treatment comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol and dicalcium phosphate.
• a method for treating cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a).
• a method for treating cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol.
• a method for treating cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias (including ALL and CML), multiple myeloma and lymphomas in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol and dicalcium phosphate.
• a method for treating lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and acute myeloid leukaemia in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a).
• a method for treating lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and acute myeloid leukaemia in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol.
• a method for treating lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumours of the central nervous system and their metastases, and acute myeloid leukaemia in a warm blooded animal such as man that is in need of such treatment which comprises administering an effective amount of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol and dicalcium phosphate.
• the in vivo effects of a compound of formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a).
• the in vivo effects of a compound of formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol.
• the in vivo effects of a compound of formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5a) with mannitol and dicalcium phosphate.
• the invention further relates to combination therapies wherein a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) is administered concurrently or sequentially or as a combined preparation with another treatment of use in the control of oncology disease.
• the invention further relates to combination therapies wherein a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol is administered concurrently or sequentially or as a combined preparation with another treatment of use in the control of oncology disease.
• the invention further relates to combination therapies wherein a pharmaceutical composition which comprises a fumarate salt of a compound of formula (5 a) with mannitol and dicalcium phosphate is administered concurrently or sequentially or as a combined preparation with another treatment of use in the control of oncology disease.
• the treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy.
• the compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of cancer.
• therapeutic agents may include one or more of the following categories of anti-tumour agents :-
• antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin- C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine
• cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5* -reductase such as finasteride; (iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6- chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperaz
• inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol.
• inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4- amine (gef ⁇ tinib, ZD 1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4- amine (erlotinib, OSI 774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of
• vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
• antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
• gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy; and
• immunotherapy approaches including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using anti idiotypic antibodies.
• cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor
• RT room temperature (approximately 17 to 25 0 C); tPv retention time; m/z mass/charge ratio.
• the film-coat may be supplied as a proprietary concentrate (eg, Opadry, product identifier 85F38196) or powder mixture that requires reconstitution in purified water, prior to application as an aqueous suspension to the tablet cores.
• a proprietary concentrate eg, Opadry, product identifier 85F38196
• powder mixture that requires reconstitution in purified water, prior to application as an aqueous suspension to the tablet cores.
• Hardness Hardness testing was carried out using a Schleuniger Hardness Tester Model 6D or equivalent, in accordance with the procedure specified in the European Pharmacopoeia (Resistance to crushing of tablets), except that the number of tablets tested was as specified in the table. The hardness of each tablet was measured along its diameter. The average 'hardness' is reported in kiloponds (kp).
• Disintegration time was measured out in accordance with the procedure specified in the European Pharmacopoeia, without a disc and using water as the medium. Disintegration time is reported in minutes (min.).
• the Compound of Formula 5 a, Aldehyde, and total impurities contents were determined using High Performance Liquid Chromatography HPLC. 5 ⁇ L sample was injected into a mobile phase comprising 0.1% trifluoroacetic acid in water (Eluent A) / 0.1% trifluoroacetic acid in acetonitrile (Eluent B), as defined by the gradient program in Table 2 below.
• the solution for the impurities determination is prepared by extraction from a known weight of 5 whole tablets using 1 :1 acetonitrile: water as extraction solvent, followed by filtration through a 0.45 micron PVDF filter, such that the target concentration of Formula 5a fumarate in the test solution is 0.6mg/mL.
• Table 2 Gradient program - Compound Assay Test
• the mobile phase starts as 80% eluent A / 20% eluent B at time zero, then the composition is modified gradually and linearly such that after 16 minutes the mobile phase comprises 70% eluent A and 30% eluent B. A steeper linear gradient is then applied such that after 26 minutes the mobile phase comprises 10% eluent A and 90% eluent B.
• the eluent composition is adjusted to80% eluent A / 20% eluent B and held from 26 minutes to 30 minutes in order to re-equilibrate the column.
• Dissolution was determined according to the general procedure of the United States Pharmacopoeia (USP) using Apparatus 2 with 90OmL of 0.02 M sodium acetate buffer at pH 4.5 as dissolution medium and a stirrer speed of 75rpm. At 15, 30 and 45 minutes, 10 ml of dissolution media was withdrawn and filtered through an unused 0.45 ⁇ m polypropylene filter. The amount of Formula 5a in solution was determined by uv spectroscopy at a wavelength of 365nm against an external standard solution comprising Formula 5a free base. Friability
• 6-Aminouracil (2.5Og, 19.1 mmol) was added to glacial acetic acid (24.6 mL) and water (6.1 mL) and the mixture heated to 99°C.
• a solution of 5-[(2E)-3-(dimethylamino)prop-2- enoyl]-2-methoxybenzyl pivalate (3.1g, 9.5 mmol) in DMSO (9.2 mL) was then added over 280 minutes. The reaction was stirred at 99°C for a further 50 minutes and cooled to 0 0 C.
• a solution of potassium hydroxide (24g, 363.6 mmol) in water (48mL) was then added to achieve a pH of around 7.0.
• Aqueous potassium carbonate was then added to afford a pH of around 10. After an hour at RT, a beige solid was filtered off, washed three times with aqueous potassium carbonate and pulled visibly dry on the filter. The beige solid was then added to a solution of citric acid (7.Ig) in water (44ml) and the mixture maintained at 20 0 C for 60 minutes. The resulting creamy white solid was isolated by filtration and washed with water until neutral pH of the wash liquors was obtained. The solid was dried to constant weight in vacuo thus affording 3.34g of desired product (3).
• 6-Aminouracil (2.69g, 22.5 mmol) was added to glacial acetic acid (55.2 mL) and water (13.8 mL) and the mixture heated to 95°C.
• a solution of 5-[(2E)-3-(dimethylamino)prop- 2-enoyl]-2-methoxybenzyl pivalate (6.25g, 18.79 mmol) in DMSO (18 mL) was then added over 240 minutes.
• Tetrahydrofuran (13.9mL) was then added and the solution cooled to 5°C.
• the resulting yellow solid was isolated by filtration, washed with fresh tetrahydrofuran (13.9mL) and dried visibly dry on the filter.
• the resulting solid was further dried to constant weight in vacuo at 70 0 C affording 6.55g of 5-(2,4-dichloropyrido[2,3- ⁇ i]pyrimidin-7-yl)-2-methoxybenzyl pivalate (4).
• the structure of the desired compound was confirmed by 1 H NMR analysis.
• Methyl 5-acetyl-2-methoxybenzoate (11.98 g, 48.0 mmol) was added to N 5 N- dimethylformamide dimethyl acetal (44.6 g, 374.5 mmol) held under a nitrogen atmosphere. The resulting solution was heated at 95°C for 60 minutes. Methanol (10ml) was then removed by atmospheric distillation and further N,N-dimethylformamide dimethyl acetal (8.90 g, 74.9 mmol) added. The resulting solution was heated at 95°C for a further 270 minutes. The reaction was then cooled to 50 0 C and ethyl acetate (35mL) added.
• 6-Aminouracil 14.32g, 112.7 mmol was added to glacial acetic acid (112.5mL) and water (75mL) and the mixture heated to 99°C.
• a solution of methyl 5-[(2E)-3- (dimethylamino)prop-2-enoyl]-2-methoxybenzoate (15g, 56.3 mmol) in DMSO (75 mL) was then added over 180 minutes. The reaction was stirred at 99°C for a further 90 minutes and cooled to 60 0 C. Water (75mL) was then added and the reaction maintained at 60 0 C for a further 60 minutes and then filtered off to afford a beige solid. The solid was washed with fresh water (75mL) and dried visibly dry thus affording 19.6g of water wet solid (9).
• a powder X-ray diffraction pattern was recorded using a Bruker D5000 diffractometer (wavelength of X-rays 1.5418 A Cu source, Voltage 4OkV, filament emission 4OmA). Samples were scanned from 2-40° 2 ⁇ using a 0.02° step and a 1 second per step time count, (see Figure 1)
• M.pt Begins to decompose from about 128 0 C onwards forming a resin.
• a powder X-ray diffraction patterns was recorded using a Bruker D5000 diffractometer (wavelength of X-rays 1.5418 A Cu source, Voltage 4OkV, filament emission 4OmA). Samples were scanned from 2-40° 2 ⁇ using a 0.02° step and a 1 second per step time count, (see Figure 2) Peaks were observed at:
• TGA was recorded using a TA Instrument TGA, Q5000 series. Typically less than 5mg of material, contained in a lOO ⁇ l platinum pan, was heated over the temperature range 25°C to 325°C at a constant heating rate of 10 0 C per minute. A nitrogen purge gas was used with flow rate 100ml per minute. The material exhibited a loss of 4.4% up to 5O 0 C followed by an additional loss of 1.7% between 70 and 14O 0 C suggesting that the material is solvated.
• Samples were scanned from 2-40° 2 ⁇ using a 0.02° step and a 1 second per step time count.
• Powder X-ray diffraction pattern was recorded on a Bruker D8 diffractometer (wavelength of X-rays 1.5418 A Cu source, Voltage 4OkV, filament emission 40 niA) with the humidity stage attached. XRD patterns were recorded under varying humidity conditions; the material was scanned from 5-40° 2 ⁇ using a step size of 0.014° and a 0.2 seconds per step time count, (see Figure 4 - Form A)
• a 10-30mg of Form A material was added to a sample vial, along with a sufficient volume of water to achieve mobility without completely dissolving the sample.
• a magnetic flea was then added and the vial was placed on a stirrer plate at room temperature to stir at approximately 200-3 OOrpm for 5 weeks.
• the slurry was then isolated and analysed by XRPD. Measurements were made using a Bruker D4 diffractometer (wavelength of X- rays 1.5418 A Cu source, Voltage 4OkV, filament emission 40 niA), samples are spun at 30 rpm to improve counting statistics. XRPD patterns were collected over the range 2° to 40° ⁇ using a step size of 0.00570° and a 0.03 second per step count time.
• DSC Typically less than 5mg of material contained in a sample pan was heated over the temperature range 25°C to 300 0 C at a constant heating rate of 10 0 C per minute. A purge gas using nitrogen was used - flow rate 100ml per minute.
• Seed crystals of Formula 5a Fumarate are added to the filtrates to initiate crystallisation.
• the resulting suspension is held at 60 0 C for 2 hours to establish crystallisation and the growth of suitably sized crystals.
• the desired product precipitated out on further cooling of the suspension.
• the product was isolated, washed with methylated spirit industrial 74 O. P. and dried to yield 10.12g of (5- ⁇ 2,4-Bis[(35)-3-methylmorpholin-4-yl]pyrido[2,3- J]pyrimidin-7-yl ⁇ -2- methoxyphenyl)methanol Fumarate as a yellow solid.
• the stability of the fumarate salt of the compound of Formula 5 a in the solid state was investigated for samples stored at 25°C/60% relative humidity (RH) in double lined polyethylene bags inside a f ⁇ breboard outer for long term stability testing.
• RH relative humidity
• accelerated and stressed stability testing was performed at 40°C/75% RH and 50 0 C AH (ambient humidity) in double lined polyethylene bags inside f ⁇ breboard outers.
• Further stress testing was performed on exposed samples at 40°C/75% RH and at ambient temperature in a light chamber (exposed to a minimum of 1.2 million lux hours visible light and 200 watt-hours/m 2 UV light), as shown in Table 5.
• composition and process selection study Tablets were manufactured using wet granulation and direct compression processes, using the fumarate salt of a compound of Formula 5 a and the compositions shown in Table 6.
• the powdered ingredients (other than the lubricant) were charged to a suitable blender and mixed to produce a uniform distribution of drug substance (the fumarate salt of the compound of Formula 5a ).
• the lubricant was added to the mixture prior to additional blending.
• the blend was compressed into tablet cores using a single station press to give tablets of the required hardness, disintegration and appearance.
• the powdered ingredients (other than the lubricant) were charged to a suitable mixer and mixed to produce a uniform distribution of drug substance (Formula 5a fumarate salt). Water was added gradually to the powders with further mixing until a suitable wet mass was formed. The resultant granules were dried to an appropriate moisture content (less than 2% by weight). The dry granules were then passed through a suitable screen (mesh size 1.0mm), before the lubricant was then added prior to blending. The blended granules were compressed into tablet cores using a single station press to give tablets of the required hardness, disintegration and appearance. Table 7 Compositions for composition and process selection study
• DCPD or DCPA 1 37.5 15 37.5 15
• a composition comprising 25% Formula 5 a fumarate salt, without a binder, was selected for further study.
• Tablet cores of 10 and lOOmg strength active agent were prepared and coated with a yellow film coating having a high content of iron oxide pigment and were investigated in a stability study varying temperature and humidity.
• a lOmg tablet composition is shown in Table 9.
• the tablets may be prepared using the following wet granulation process:
• the granules were dried in a Vector FLM-3 fluid bed dryer (inlet air temperature 60 0 C, air flow rate sufficient to fluidise the granule bed) to a moisture content of ⁇ 2% w/w and the dried granules milled using a Quadra Comil 194 (screen mesh 0.062 inches (1.6 mm), 400rpm).
• H-X coater (15 inch drum) with Opadry II Yellow (Colorcon 85F38196, 200 g/kg aqueous solution).
• the total coating solution applied is equivalent to 40g/kg of Opadry per mass of tablet cores.
• a lOOmg tablet composition is shown in Table 10.
• Tablet coating (A) mg / % of coating weight Function tablet
• Nominal coatine weieht 20.0 4.0 The lOOmg tablets may be prepared using an analogous method to that described for the preparation of the lOmg tablets shown in Table 9.
• Tablet core composition from Example 7 was selected for further study. Tablet cores of 10 and 20mg strength active agent were prepared and coated with a yellow film coating having a low content of iron oxide pigment were investigated in a photostability study.
• a lOmg tablet composition is shown in Table 12.
• the tablet cores may be prepared using, for example, the wet granulation process described previously (see Example 7). The tablet cores are then coated using an O'Hara
• a 20mg tablet composition is shown in Table 13.
• Table 13 20mg tablet (20mg Formula 5a, mannitol / dibasic calcium phosphate anhydrous filler)
• the 20mg tablets may be prepared using an analogous method to that described for the preparation of the lOmg tablet compositions shown in Table 12.
• Photostability was assessed for the 10 mg and 20 mg tablet compositions described in Tables 12 and 13 above.
• An illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours per square metre (Wh/m2) was applied to the 10 mg and 20 mg yellow film coated tablets in an open petri dish, HDPE bottles only and HDPE bottles in secondary pack consisting of a cardboard carton with cardboard liner.
• the photostability data are presented in Tables 14 and 15.
• NCH No change from initial time -point
• Titanium dioxide 4.700 23.50 Opacif ⁇ er
• Nominal coating weight 20.00 4.0 The lOOmg tablets may be prepared using an analogous method to that described for the preparation of the lOmg tablet compositions shown in Table 12.

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